The applicants propose that the skeleton's ability to adapt to functional stimuli is directly dependent on the organism's systemic state. More specifically, systemic "disorders", such as aging, nutritional deficiency or hormonal imbalance will substantially compromise bone tissues' ability to perceive and/or respond to the positive influences of mechanical stimuli in the control of bone mass. Results from the first two years of the applicant's FIRST award demonstrate that both the location and magnitude of the remodeling response to new mechanical regimes are specific to, and controlled by, the type of systemic disorder. This remodeling specificity implies that, in each systemic population, either an altered cellular population exists, or the mechanisms responsible for the perception of the mechanical milieu have been perturbed. The objective of this five year proposal is to quantify the dependence of the remodeling response on interactions between three distinct mechanical stimuli and five different systemic states: (1) growth; (2) aging: (3) nutritional deficiency: (4) endocrinopathy; and (5) "normal" adult. As the mechanical state of the functionally isolated turkey ulna preparation is accurately controlled, and the turkey's systemic state readily altered, this model will be exploited in the protocol. Five populations of turkeys will be established, four representative of one of these systemic imbalances, while a fifth "normal adult" population will serve as a control. In each of these groups, the location and magnitude of the bone tissue's remodeling response to disuse, and to two loading regimens demonstrated as osteogenic in the normal adults, will be determined at the matrix level by physical property measurement, at the cell and tissue level by static and dynamic histomorphometry, and at the organ level by changes in diaphyseal areal properties. Any alteration or attenuations in the response will be correlated to matrix, cell, tissue, and organ criteria of the intact control ulnae within each group, as well as to that which occurs in the normal. The preliminary experiments reflect a complex, rather than a simple inter-relationship between the mechanical environment and the systemic state of the organism. The proposed experiments are designed to confirm and extend these observations, to explore the selective interaction of the systemic and mechanical milieu, and to determine the potential which physical stimuli possess to combat the bone loss caused by many systemic disorders. The applicants are confident that examination of the location and magnitude in which systemically pressured bone tissue responds to mechanical stimuli will improve understanding of the multifactorial pathogenesis of osteopenia and provide new insights towards its etiology and treatment.